US10179173B2 - Semi-solid delivery systems - Google Patents

Semi-solid delivery systems Download PDF

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US10179173B2
US10179173B2 US14/387,178 US201314387178A US10179173B2 US 10179173 B2 US10179173 B2 US 10179173B2 US 201314387178 A US201314387178 A US 201314387178A US 10179173 B2 US10179173 B2 US 10179173B2
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cycloalkyl
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US20150283244A1 (en
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Chun Wang
Wenshou Wang
John R. Ohlfest
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University of Minnesota
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A61K38/385—Serum albumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C08G65/3322—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof acyclic

Definitions

  • biodegradable and biocompatible polymers have been extensively studied as drug controlled release carriers. Besides selecting the optimal polymer for specific drug delivery purpose, how to incorporate drugs efficiently into polymers is another important issue. Polymers have been prepared into different physical forms, such as micelles, nanoparticles, microspheres, films, gels, to facilitate the encapsulation and controlled release of drugs (see Uhrich, K. E., et al., Chem. Rev . 1999, 99, 3181-3198). In spite of all the advances made, there is much to be further improved. First, most micelles, microspheres or particles often have low drug loading efficiency, as low as a few percent in some cases.
  • a new semi-solid polymer based material has been identified that is a semi-solid material at room and physiological temperatures allowing easy formulation of drugs (e.g. by simple mixing) and delivery by minimally invasive injection or topical application (to the skin).
  • the material is capable of loading and releasing a wide range of drugs either hydrophobic or hydrophilic, including small molecule drugs, and macromolecular drugs such as proteins, peptides, polysaccharides, nucleic acids.
  • the polymers can be used to deliver tumor antigens and immunostimulatory adjuvants.
  • the polymer chemistry utilized for the preparation of the semi-solid polymers allows for easy tuning of drug release rate to suit different application requirement.
  • the materials have the additional advantages of being synthesized easily from biocompatible building blocks, so that the degradation products are biocompatible.
  • the materials also offer the advantage of being synthesized using commonly available molecules, so that their preparation is cost-effective.
  • the invention provides a polymer of the invention which is a polymer comprising 1) one or more units of formula Ia, IIa, or IIIa:
  • each R is independently (C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 10 )alkyl, (C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 3 -C 8 )cycloalkyl-O—(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O—(C 3 -C 8 )cycl
  • each R a is independently hydrogen, ((C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 10 )alkyl, or (C 1 -C 10 )alkyl-O—(C 1 -C 10 )alkyl.
  • the invention also provides a pharmaceutical composition comprising a polymer of the invention and a biologically active agent.
  • the polymers of the invention can be used as a controlled release system for a very broad range of cargos including small molecular drugs, large molecular drugs such as proteins (including antibodies), peptides, polysaccharides, nucleic acids, or multiple cargos of these kinds combined in a single system.
  • the material is a semi-solid so it is most suited for parenteral delivery of drugs through injection or topical application to the skin.
  • Applications include drug delivery in disease treatments that require parenteral delivery, such as cancer therapy, anti-inflammatory anti-infectious therapies, neurological drug therapy including pain relieve, vaccine formulation and adjuvant delivery, and drug therapies to treat skin disorders and metabolic diseases such as diabetes.
  • the invention also provides processes and intermediates disclosed herein that are useful for preparing the polymers of the invention.
  • FIG. 1 Illustrates the synthesis of a representative polymer of the invention.
  • FIG. 2 Illustrates proton NMR data for the compounds and polymers synthesized in Example 1.
  • FIG. 3 Illustrates Rheological studies and injectability of the semi-solid polymers.
  • A Frequency sweep of PCL-OE-1 at various temperature
  • B Frequency sweep of PCL-OE-2 at various temperature
  • C Compound viscosity and temperature dependence of viscosity are dependent on polymer composition (shear frequency was 1 Hz). Compound viscosity of the polymers was measured at different temperature and shear frequency. As temperature increased, polymer viscosity decreased sharply. At constant temperature, the polymer maintained constant viscosity without substantial thinning or thickening. Viscosity of the polymers was dependent on the polymer composition. Both polymers were injectable at room or physiological temperature through a needle.
  • FIG. 4 Illustrates hydrolysis data of the semi-solid polymers measured by the loss of polymer mass over time in aqueous buffer of different pH.
  • A PCL-OE-1
  • B PCL-OE-2.
  • polymer degradation rate was dependent on polymer composition.
  • PCL-OE-2 degraded faster than PCL-OE-1.
  • FIG. 5 Illustrates toxicity data in fibroblast cells in vitro after incubating cells with semi-solid polymer for 24 hours. There was no toxicity, even with polymer concentration as high as 1 mg/mL.
  • FIG. 6 Illustrates release kinetics of a small molecule hydrophobic drug (Ibu) and a hydrophilic model protein drug (BSA) in aqueous media at physiological pH 7.4 and mildly acidic pH 5.0.
  • Ibu small molecule hydrophobic drug
  • BSA hydrophilic model protein drug
  • FIG. 7 Shows results for the injection of the semi-solid polymer (PCL-OE-1) subcutaneously in mice over 2 weeks. No visible tissue damage or inflammatory response was seen from the H&E stained tissue sections.
  • FIG. 8 (A) GPC traces of semi-solid samples after 1 and 2 weeks of implantation in mice. After 1 week some of the short chain polymers were lost but the majority of the polymer was yet to degrade. After 2 weeks there was marked degradation of the polymer, resulting in a shift in the peak position and the appearance of short polymer chains; (B) Proton NMR analysis of the semi-solid polymer after 1 and 2 weeks of implantation in mice. Shown are characteristic peaks of ortho ester protons (h) and PCL protons (e). The ortho ester bond and the PCL structure in the remaining polymer are largely intact. The ability of maintaining structural stability in vivo for considerable amount of time supports the utility of the polymer for sustained drug delivery.
  • FIG. 9 Illustrates antigen-specific antibody response following administration of a composition comprising a polymer of the invention and a combination of OVA and RES. Mice treated with the combination of OVA and RES delivered via the semi-solid polymer had high intensity and sustained antibody responses through at least day 77. Antibodies are key factors in the generation and maintenance of helper T-cell responses. CD4+ helper T-cells have been shown to play a critical role in the therapeutic immune response, having demonstrated cytolytic activity. CD4 cells can be more efficient at tumor rejection than CD8 cells.
  • FIG. 10 Illustrates antigen-specific CD8 T cell response following administration of a composition comprising a polymer of the invention and a combination of OVA and RES.
  • Mouse to mouse variability in the intensity and duration of immune response is found within all the treatment groups. However, a number of mice (5/12) in the polymer group showed maintenance of OVA-specific CD8 T-cells above standard treatment levels at 4 months post-vaccination. Even more encouraging is the upward trend in % OVA-specific CD8 cells in 4/5 of those mice on day 115. Sustainment of recall response and cytolytic ability are currently being tested.
  • FIG. 11 Illustrates antigen-specific CD8 T cell response following administration of a composition comprising a polymer of the invention and a combination of OVA and RES.
  • the data in FIG. 11 was analyzed by calculating area under the curve (AUC) from day 0 through day 115 for each mouse.
  • AUC area under the curve
  • the results represent the average cumulative exposure to OVA-specific CD8+ T-cells in each group.
  • total exposure to cytotoxic T-cells may prove to be an important predictor of treatment outcome, which makes the analysis of AUC here more meaningful and informative. It is clearly seen here that the single injection of semi-solid formulation of the antigen and adjuvant achieved significantly higher T cell response than all other treatment groups.
  • FIG. 12 Illustrates the synthesis of a representative polymer of the invention.
  • FIG. 13 Illustrates data from Example 3 that shows that the compound viscosity and temperature dependence of viscosity are dependent on polymer composition. Shear frequency was 1 Hz.
  • FIG. 14 Illustrates the mass loss of PCL-PEG-OE-1 in aqueous buffers of pH 7.4 and pH 5.0. Note that by the inclusion of PEG, the erosion rate of this polymer is much faster than PCL-OE-1. For PCL-PEG-OE-1, it only took one day to reach remaining mass of below 40%, whereas for PCL-OE-1, it took many days.
  • FIG. 15 Proton NMR analysis of PCL-PEG-OE-1 degradation in aqueous buffer of pH 5.0. As the ortho ester bond is cleaved, peak a diminishes substantially from 4 h to 24 h, whereas peak b of the PCL segment does not change significantly.
  • FIG. 16 Proton NMR analysis of PCL-PEG-OE-1 hydrolysis: the ratio of peak area b/a, representing the degree of ortho ester hydrolysis of the polymer, increased substantially with time at pH 5.0 but changed little over time at pH 7.4. This observation is consistent with the measurement of mass loss at different pHs (shown in FIG. 16 ).
  • FIG. 17 Illustrates cytotoxicity data for the PCL-PEG-OE polymers.
  • the polymers are essentially nontoxic even at concentrations as high as 1 mg/mL.
  • the cytotoxicity test was conducted on NIH 3T3 mouse fibroblasts treated with polymers for 24 h
  • FIG. 18 The PCL-PEG-OE polymers were dispersed in PBS buffer (pH 7.4) at 1 mg/mL and the average particle size of the suspensions was measured using dynamic light scattering. Because polymer 1 contained more PEG segment than polymer 2, it was able to form nanoparticles with diameter under 100 nm, which remained stable in pH 7.4 for at least 24 h. Therefore, the dispersion of the semi-solid polymer into large excess of aqueous buffer forming nanoparticles is a distinct feature of the PCL-PEG-OE polymers, which are amphiphilic in nature.
  • FIG. 19 PCL-PEG-OE-1 nanoparticles in water undergo temperature responsive phase transition. At temperature below ⁇ 35° C., the 1 mg/mL solution of the nanoparticles was optically clear, however, it turned cloudy as temperature raised up to 36° C. The temperature responsive phase transition behavior was also reversible. This temperature responsive behavior around the range of room temperature to physiological temperature is unique to the PCL-PEG-OE type of polymer; it was not observed with the PCL-OE polymers. This behavior suggests the possibility of using the nanoparticles as hyperthermia-controlled drug delivery vehicles.
  • FIG. 20 Shows that Nile Red loaded PCL-PEG-OE-1 nanoparticles were smaller than 100 nm and remained stable in pH 7.4 aqueous buffer for at least 8 h, as observed by dynamic light scattering.
  • halo is fluoro, chloro, bromo, or iodo.
  • Alkyl denotes both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • POE-CL polyorthoester-caprolactone
  • PCL-OE polycaprolactone-orthoester
  • (C 1 -C 10 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, or decyl; and (C 3 -C 8 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.
  • the polymers of the invention can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, e.g., topical or injection.
  • the polymers can be administered by injection in pure liquid form, or as solutions, or as dispersions.
  • Solutions of the polymers can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, buffers or sodium chloride.
  • Sterile injectable solutions can be prepared by incorporating the polymers in the required amount, either in pure liquid form, or in the appropriate solvent with other ingredients enumerated above, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • compositions may be applied in pure form. However, they may also be administered to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier.
  • Useful dosages of the biologically active agents can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the biologically active agent required for use in treatment will vary not only with the particular biologically active agent selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • Polymers of the invention can be prepared using techniques that are similar to those described herein or they can be prepared using techniques that are known.
  • polymers of the invention can be prepared using procedures similar to those that are described in Examples 1 and 3 and are illustrated in FIGS, 2 , and 12 .
  • a compound with divicinyl diol such as 1,4-cyclohexanedimethanol bis(1,2-propane diol) ether (Compound 1, FIG. 1 ) was synthesized via hydrolysis of the corresponding 1,4-cyclohexanedimethanol diglycidyl ether with 100% conversion [Jiang, J.; Xiu, Z.; Hua, R.
  • Representative polymers of the invention include polymers having the following structures:
  • the invention provides polymers that comprise one or more units of formula Ib, IIb, or IIIb:
  • each A is independently a unit comprising polycaprolactone.
  • A is a homopolymer of caprolactone.
  • the invention provides polymers that comprise one or more units of formula Ic, IIc, or IIIc:
  • each A is independently a polymer comprising polycaprolactone and each D is a unit comprising polyethylene oxide.
  • A is a homopolymer of caprolactone.
  • D is a homopolymer of ethylene oxide.
  • polymers of the invention do not comprise one or more units of polyethyleneoxide.
  • the invention provides polymers that comprise one or more units of formula Ia.
  • the invention provides polymers that comprise one or more units of formula IIa.
  • the invention provides polymers that comprise one or more units of formula IIIa.
  • the invention provides polymers that comprise repeating units of formula Ib, IIb, or IIIb.
  • the invention provides polymers that comprise repeating units of formula Ic, IIc, or IIIc.
  • R is (C 2 -C 10 )alkyl.
  • R is ethyl, propyl, butyl, pentyl, or hexyl.
  • R is ethyl, propyl, butyl, pentyl, or hexyl.
  • R is (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl.
  • R x is cyclohexyl or —CH 2 CH 2 —.
  • each R is independently (C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 10 )alkyl, or (C 1 -C 10 )alkyl-O—(C 1 -C 10 )alkyl.
  • each R is independently (C 1 -C 10 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl(C 1 -C 10 )alkyl, or (C 1 -C 10 )alkyl-O—(C 1 -C 10 )alkyl; and each A is independently a homopolymer or copolymer comprising polycaprolactone.
  • the polymer of the invention has a molecular weight of at least about 2000.
  • the polymer of the invention has a molecular weight of at least about 5000.
  • the polymer of the invention has a molecular weight of at least about 10,000.
  • the polymer of the invention has a molecular weight of less than about 50,000.
  • the polymer of the invention has a molecular weight of less than about 30,000.
  • the polymer of the invention has a molecular weight of less than about 20,000.
  • the polymer of the invention has a molecular weight of 15,000 ⁇ 10,000.
  • the polymer of the invention has a molecular weight of 15,000 ⁇ 5,000.
  • the polymer of the invention has a molecular weight of 20,000 ⁇ 5,000.
  • Polymers of the invention are useful as carriers for a variety of biologically active agents.
  • the release of the biologically active agents from the polymers of the invention can be modified by blending the semi-solid polymer with buffer salts that control the pH environment. Another way is to control the molecular weight of the PCL segment. Yet another method is to change the structure of R. For example, in Example 1, the starting material 1,4-cyclohexanedimethanol diglycidyl ether can be replaced by 1,4-butanediol diglycidyl ether, and the resulting semi-solid polymer will have a faster degradation rate.
  • PCl can be synthesized via ring opening polymerization of caprolactone using well-known methods. See: Labet M, Thielemans W, Synthesis of polycaprolactone: a review. Chem Soc Rev. 2009, 38(12), 3484-3504. Many PCL diols are commercially available.
  • the invention provides polymers that have one or more ortho-ester containing units of formula Ia, IIa, or IIIa, and one or more units that comprise polycaprolactone.
  • the unit that comprises polycaprolactone is a homopolymer of caprolactone.
  • n is an integer from 1-10 and m is an integer from 1-10.
  • the unit that comprises polycaprolactone is a copolymer of caprolactone and one or more other polymers that can be synthesized from ring opening polymerization.
  • R 1 is (C 1 -C 10 )alkyl, or (C 1 -C 10 )alkenyl containing 1 to 3 double bonds
  • R 2 is hydrogen, (C 1 -C 10 )alkyl, or (C 1 -C 10 )alkenyl containing 1 to 3 double bonds, wherein the position at which R 2 is connected to R 1 can be at the ⁇ , ⁇ , ⁇ , ⁇ , ⁇ carbon of R 1 ;
  • m is an integer from 1-20; and n is an integer from 1-20.
  • At least 0.1 mol % of the unit that comprises polycaprolactone is polycaprolactone.
  • At least 1 mol % of the unit that comprises polycaprolactone is polycaprolactone.
  • At least 10 mol % of the unit that comprises polycaprolactone is polycaprolactone.
  • At least 25 mol % of the unit that comprises polycaprolactone is polycaprolactone.
  • At least 50 mol % of the unit that comprises polycaprolactone is polycaprolactone.
  • the molecular weight of the unit that comprises polycaprolactone is at least 50.
  • the molecular weight of the unit that comprises polycaprolactone is at least 100.
  • the molecular weight of the unit that comprises polycaprolactone is at least 150.
  • the molecular weight of the unit that comprises polycaprolactone is at least 500.
  • the molecular weight of the unit that comprises polycaprolactone is at least 1000.
  • the molecular weight of the unit that comprises polycaprolactone is 3000 ⁇ 2000.
  • the molecular weight of the unit that comprises polycaprolactone is less than 5000.
  • the molecular weight of the unit that comprises polycaprolactone is less than 3000.
  • the molecular weight of the unit that comprises polycaprolactone is less than 2000.
  • the molecular weight of the unit that comprises polycaprolactone is less than 1000.
  • “A” is a homopolymer of caprolactone.
  • n is an integer from 1-10 and m is an integer from 1-10.
  • “A” is a copolymer of caprolactone and one or more other polymers that can be synthesized from ring opening polymerization.
  • R 1 is (C 1 -C 10 )alkyl, or (C 1 -C 10 )alkenyl containing 1 to 3 double bonds
  • R 2 is hydrogen, (C 1 -C 10 )alkyl, or (C 1 -C 10 )alkenyl containing 1 to 3 double bonds, wherein the position at which R 2 is connected to R 1 can be at the ⁇ , ⁇ , ⁇ , ⁇ , ⁇ carbon of R
  • m is an integer from 1-20
  • n is an integer from 1-20.
  • At least 0.1 mol % of A is polycaprolactone.
  • At least 1 mol % of A is polycaprolactone.
  • At least 10 mol % of A is polycaprolactone.
  • At least 25 mol % of A is polycaprolactone.
  • At least 50 mol % of A is polycaprolactone.
  • At least 75 mol % of the unit that comprises polycaprolactone is polycaprolactone.
  • At least 90 mol % of the unit that comprises polycaprolactone is polycaprolactone.
  • At least 95 mol % of the unit that comprises polycaprolactone is polycaprolactone.
  • At least 99 mol % of the unit that comprises polycaprolactone is polycaprolactone.
  • the molecular weight of “A” is at least 50.
  • the molecular weight of “A” is at least 100.
  • the molecular weight of “A” is at least 150.
  • the molecular weight of “A” is at least 500.
  • the molecular weight of “A” is at least 1000.
  • the molecular weight of “A” is 3000 ⁇ 2000.
  • the molecular weight of “A” is less than 5000.
  • the molecular weight of “A” is less than 3000.
  • the molecular weight of “A” is less than 2000.
  • the molecular weight of “A” is less than 1000.
  • the invention provides polymers that have one or more ortho-ester containing units of formula Ia, IIa, or IIIa; one or more units that comprise polycaprolactone; and optionally one or more units that comprise polyethyleneoxide (PEO or PEG).
  • At least 0.1 mol % of the unit that comprises polyethyleneoxide is polyethyleneoxide.
  • At least 1 mol % of the unit that comprises polyethyleneoxide is polyethyleneoxide.
  • At least 10 mol % of the unit that comprises polyethyleneoxide is polyethyleneoxide.
  • At least 25 mol % of the unit that comprises polyethyleneoxide is polyethyleneoxide.
  • At least 50 mol % of the unit that comprises polyethyleneoxide is polyethyleneoxide.
  • At least 75 mol % of the unit that comprises polyethyleneoxide is polyethyleneoxide.
  • At least 90 mol % of the unit that comprises polyethyleneoxide is polyethyleneoxide.
  • At least 95 mol % of the unit that comprises polyethyleneoxide is polyethyleneoxide.
  • At least 99 mol % of the unit that comprises polyethyleneoxide is polyethyleneoxide.
  • the molecular weight of the unit that comprises polyethyleneoxide is at least 50.
  • the molecular weight of the unit that comprises polyethyleneoxide is at least 100.
  • the molecular weight of the unit that comprises polyethyleneoxide is at least 150.
  • the molecular weight of the unit that comprises polyethyleneoxide is at least 500.
  • the molecular weight of the unit that comprises polyethyleneoxide is at least 1000.
  • the molecular weight of the unit that comprises polyethyleneoxide is less than 2000.
  • the molecular weight of the unit that comprises polyethyleneoxide is less than 1000.
  • the molecular weight of the unit that comprises polyethyleneoxide is 500 ⁇ 250.
  • the molecular weight of the unit that comprises polyethyleneoxide is at least 50.
  • the molecular weight of the unit that comprises polyethyleneoxide is at least 100.
  • the molecular weight of the unit that comprises polyethyleneoxide is at least 150.
  • the molecular weight of D is at least 500.
  • the molecular weight of D is at least 1000.
  • the molecular weight of D is less than 2000.
  • the molecular weight of D is less than 1000.
  • the molecular weight of D is 500 ⁇ 250.
  • Polymers of the invention can be used to deliver a variety of biologically active agents.
  • agents include therapeutic agents (including small molecule drugs) and macromolecules (such as proteins, peptides, polysaccharides, and nucleic acids).
  • the polymers of the invention can be used to deliver agents that are useful for cancer therapy (anticancer drugs), anti-inflammatory therapy, anti-infectious therapy (such as antibiotics), neurological drug therapy including anesthetics for pain relief, antiangiogenic drugs, polysaccharides, vaccines, antigens, antibodies, cytokines, DNA and other polynucleotides, antisense oligonucleotides, RNA including small interfering RNA, and the like, and therapies to treat skin disorders and metabolic diseases such as diabetes.
  • cancer therapy anticancer drugs
  • anti-inflammatory therapy such as antibiotics
  • anti-infectious therapy such as antibiotics
  • neurological drug therapy including anesthetics for pain relief, antiangiogenic drugs, polysaccharides, vaccines, antigens,
  • the polymers of the invention can also be used to deliver locally active agents such as astringents, antiperspirants, irritants, rubefacients, vesicants, sclerosing agents, caustics, escharotics, keratolytic agents, sunscreens and a variety of dermatologics including hypopigmenting and antipruritic agents.
  • Other agents that can be delivered by this polymer includes biocides such as fungicides, pesticides, and herbicides, plant growth promoters or inhibitors, preservatives, disinfectants, air purifiers and nutrients. See for example U.S. Pat. No. 6,613,355.
  • Antigens that could be used at a dose of 1-1,000,000 ⁇ g or protein or cell number could include tumor cells (irradiated, frozen, lysed, dried), tumor-associated peptides, tumor neoantigens that result from genetic mutation in the somatic tumor cells, aberrantly glycolsylated tumor proteins, tumor cell membranes, or DNA encoding any of the above.
  • Adjuvants that could be used at a dose of 1-1,000,000 ⁇ g: toll-like receptor agonists such as but not limited to CpG, PolyIC, Imiquimod (or any imidazoquinoline-derivative of Imiquimod), Resiquimod, Flagellin.
  • toll-like receptor agonists such as but not limited to CpG, PolyIC, Imiquimod (or any imidazoquinoline-derivative of Imiquimod), Resiquimod, Flagellin.
  • the rheological behavior of the polymers was measured with an AR-G2 rheometer (TA Instrument, Ltd) equipped with parallel plate geometry (25 mm diameter). The gap between parallel plates was adjusted to around 1 mm. The dynamic strain sweep measurement was first performed to ensure that the materials were in their linear viscoelastic range and then the small amplitude oscillatory shear was conducted over a temperature range of 20° C. to 80° C.
  • the cytocompatibility of the semi-solid polymers was evaluated by an MTT (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay.
  • Fibroblast cells NASH3T3
  • NASH3T3 Dulbecco's Modified Eagle Medium supplemented with 10% FBS, 10 mM HEPES, 100 U/mL penicillin/streptomycin at 5% CO 2 and 37° C.
  • MTT in PBS 5 mg/mL, 20 mL was added to each well reaching a final concentration of 0.5 mg/mL.
  • a certain amount of drugs (Ibuprofen or BSA) were grinded into fine particles and then mixed with certain amount of polymer in a glass vial. The mixtures were manually stirred for about 20 minutes and then place on the bench overnight before use.
  • the drug release behavior of polymers was measured as the following: around 50 mg of drug loaded polymer (5 wt %) was placed in small nylon bags (200 mesh) and immersed in 6 mL of buffered saline (pH 7.4 or 5.0). At certain time points, the buffer was removed for analysis and replaced with fresh buffer.
  • the amount of Ibu released in the medium was measured by UV spectroscopy (Beckman Coulter, DU 640B spectrophotometer) for absorbance at 263 nm.
  • the BSA concentration was measured by the absorbance at 595 nm with a Quick StartTM Bradford Protein Assay kit.
  • the Feed composition, average molecular weight, and glass transition temperature of the semi-solid polymers prepared in Example 1 are provided in Table 1.
  • FIGS. 1-7 Analytical data and assay results for the compounds prepared in Example 1 are shown in FIGS. 1-7 .
  • An anti-inflammatory drug, Ibu was loaded into the semi-solid polymer (PCL-OE-1) by simple dissolution.
  • Ibu is a small molecular drug with poor solubility in water.
  • the semi-solid polymer provides excellent solubility for Ibu, resulting in a clear solution.
  • a model protein drug, BSA is highly water soluble, and was also incorporated with the semi-solid polymer by mixing fine particles of the protein. The opaque suspension of BSA particles in the semi-solid polymer maintained excellent injectability.
  • Vaccines have recently been approved by the FDA for the prevention of cervical cancer and treatment of castration-resistant prostate cancer. Despite these early success stories, the majority of cancer vaccines tested in clinical trials have generated modest clinical responses and suboptimal immune responses. The vast majority of these vaccines involve acute injection of tumor antigen and immune adjuvant that is rapidly degraded. This acute delivery approach has yielded low-level and transient tumor-reactive T cells frequencies and weak antibody titers, relative to real viral infections that prime massive immune responses and take days-to-weeks to clear.
  • the biodegradable polymers of the invention can be used to provide a sustained delivery vaccine similar to a real viral infection, resulting in more robust and long-lasting T and B cell responses.
  • mice Female C57BL/6 (BL6) mice (6-8 weeks old) were purchased from Jackson Laboratory and maintained in a specific pathogen-free facility according to the guidelines of the University of Minnesota Animal Care and Use Committee.
  • soluble ovalbumin (OVA) protein, a model antigen, and Resiquimod (RES) were delivered in 1% DMSO in phosphate buffered saline (PBS).
  • PBS phosphate buffered saline
  • Semi-solid polymer (PCL-OE-1) formulations were prepared by mixing lyophilized OVA powder with the polymer to generate a dispersion. RES was directed dissolved into the semi-solid polymer. The antigen/adjuvant formulation was mixed by stirring for 10 min and allowed to settle overnight at 4° C. before use.
  • mice were vaccinated subcutaneously in the right inguinal region with either 50 ⁇ L of either 0.9% saline once daily for four consecutive days, OVA protein (200 ⁇ g) plus RES (50 ⁇ g) in 1% DMSO once daily for four consecutive days, or a single injection with semi-solid polymer plus OVA (800 ⁇ g) and RES (200 ⁇ g). All formulations were freshly prepared at the time of vaccination.
  • a total of 50 ⁇ L of whole blood was stained with MHC class I-OVA dextramer (Immundex) at 4° C. for 30 minutes followed by staining with PerCp-Cy5.5-conjugated anti-CD8 (eBioscience) at 4° C. for 1 hour. Red blood cells were lysed and cells were washed twice with PBS and re-suspended in FACS buffer followed by analysis using a FACSCanto II. Data were further analyzed with FlowJo software (Tree Star). Plots were generated from Prism (GraphPad Software, Inc). Analysis gates were set based on the PerCp-Cy5.5 positive population. The percentage of OVA-specific CD8 T-cells was calculated based on the percentage of cells stained with MHC-I/OVA dextramer within the CD8+ population.
  • OVA protein was plated at 0.5 ⁇ g/ml in PBS (100 ⁇ L/well) in 96-well flat bottom plates and incubated overnight at 4° C. Each well was washed with 2% fraction V BSA/PBS (100 ⁇ L/well) for 60 min at room temperature. Wells were then washed once with 0.5% fraction V BSA/PBS (200 ⁇ L/well). Plasma samples were then added to the wells at a 1:300 dilution in PBS (100 ⁇ L/well) and incubated for 2 h at room temperature. Wells were then washed three times with 0.5% fraction V BSA/PBS (200 ⁇ L/well) and once with PBS (200 ⁇ L/well).
  • Blood was collected from the periorbital vein on days 5, 7, 9, 13, 20, 27, 34, 48, 62, 77 and 100. Mice were anesthetized with 75 mg/kg i.p. for the procedure and monitored closely throughout. After collection, proparacaine 1% eye drops and triple antibiotic ointment were applied to the collection site. At each time point, 100 ⁇ L of whole blood was diluted in 50 ⁇ L of heparin (1000 units/mL). Plasma samples were prepared from 50 ⁇ L of whole blood as described. The remaining 50 ⁇ L was used the same day for flow cytometry experiments.
  • Results from Example 2 for the compounds prepared in Example 1 are shown in FIGS. 8-10 .
  • the product was dialyzed against THF with cut off molecular weight 1000 Da for 2 days to remove unreacted monomers and catalyst.
  • the final product was obtained after vacuum drying.
  • the final product was synthesized with a feed molar ratio of PCL/PEG of 1, hence named “PCL-PEG-OE-1”.
  • another polymer was also synthesized with a feed molar ratio of PCL/PEG of 2, hence named “PCL-PEG-OE-2”.
  • the molar ratio of monomer 1 and the sum of PCL and PEG was kept constant as 1.
  • the synthesis is illustrated in Figure
  • the resulting polymers were characterized by GPC, proton NMR, rheology, erosion (by mass loss), and cytotoxicity (MTT assay), using procedures similar to those described in Example 1.
  • 3 mg of the PCL-PEG-OE polymers were mixed with 3 mL of PBS (pH 7.4) at room temperature and the average hydrodynamic diameter of the nanoparticles was determined using a ZetaPlus Particle Analyzer (Brookhaven Instruments Corporation, Holtsville, N.Y.; 27 mW laser; 658 nm incident beam, 90° scattering angle).
  • the optical transparency of the nanoparticle solution was measured by UV-Vis light spectroscopy at 500 nm with a heating rate of ⁇ 1° C. per minute.
  • Nile Red (NR, 3 mg) was dissolved in 100 mg of PCL-PEG-OE-1 polymer and mixed well. After incubating at room temperature overnight, the 3% NR loaded polymer was mixed with 3 mL of PBS (pH 7.4). The nanoparticle solution was photographed and the average particle size of the NR loaded nanoparticles was measured by dynamic light scattering as described above.
  • the Feed composition, average molecular weight, and glass transition temperature of the semi-solid polymers prepared in Example 3 are provided in Table 2.

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